tbuckley/cabot-search huggingface dataset:
Abstract 2868: ADG206, an anti-CD137 agonistic POWERbody࣪ with tailor-made efficacy and safety profiles by strong crosslinking and tumor selective activation for single and combinational cancer immunotherapy
Authors: Guizhong Liu, Zhengxi Dai, Jiagui Qu, Jianfeng Shi, Qi Zhao, Linhai Qu, Yan Li, Songmao Zheng, Jiangchun Xu, Felix Du, Peter Luo
Journal: Cancer Research (2022)

Abstract Targeting CD137 by agonistic antibodies faces various challenges in the clinic. Utomilumab appears safe but has modest efficacy, while urelumab is more efficacious but causes severe dose-dependent liver toxicity. To unlock the full potential of CD137 immunotherapy, we engineered a ADG206 POWERbody࣪ by combining our SAFEbody® technology’s precision masking of the antigen binding sites with the Fc engineering in order to achieve improved safety and efficacy profiles. In normal tissues, the CD137 antigen binding interfaces of ADG206 are masked using a covalently linked designer peptide to limit on-target off-tumor toxicities, whereas in the tumor microenvironment (TME), the masked antibody can be activated to selectively bind CD137, promoting costimulatory signaling in situ. The activity of ADG206 is further heightened by incorporating Fc mutations with increased FcγR-mediated crosslinking, resulting in enhanced T cell responses and antitumor activity. In vitro nonclinical studies demonstrate that activated ADG206 binds to CD137, with agonistic activity strictly dependent on FcγR-mediated crosslinking, in contrast to FcγR-independent stimulation of CD137 by urelumab. When activated, ADG206 exhibits up to ~4-fold stronger anti-CD137 agonistic activity than urelumab for T cell activation in the presence of a primary stimulatory signal, while masked ADG206 has much lower activity. In vivo nonclinical studies demonstrate that ADG206 has robust single agent antitumor activities in multiple syngeneic murine tumor models and synergistic efficacy when combined with other immunomodulatory agents. Moreover, ADG206 is well-tolerated in rats and cynomolgus monkeys in nonclinical toxicology studies, with normal pharmacokinetic behaviors and minimal activation in circulation. These results demonstrate that ADG206 POWERbody acquires a tailor-made product profile toward a best-in-class anti-CD137 immunotherapeutic agent that combines conditional activation in the TME with strong agonistic activity through heightened FcγR-mediated crosslinking. Further clinical development of ADG206 POWERbody may hold promises for achieving the long-awaited desirable tolerability and efficacy outcome of an anti-CD137 immunotherapy in either single agent or combination regimens. Citation Format: Guizhong Liu, Zhengxi Dai, Jiagui Qu, Jianfeng Shi, Qi Zhao, Linhai Qu, Yan Li, Songmao Zheng, Jiangchun Xu, Felix Du, Peter Luo. ADG206, an anti-CD137 agonistic POWERbody࣪ with tailor-made efficacy and safety profiles by strong crosslinking and tumor selective activation for single and combinational cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2868.
Abstract 5010: Comprehensive characterization of 11 prognostic alternative splicing events in ovarian cancer interacted with the immune microenvironment
Authors: Guixi Zheng
Journal: Cancer Research (2022)

Abstract Alternative splicing (AS) events play a crucial role in the tumorigenesis and progression of cancer. Transcriptome data and Percent Spliced In (PSI) values of ovarian cancer patients were downloaded from TCGA database and TCGA SpliceSeq. Totally we identified 1,472 AS events that were associated with survival of ovarian serous cystadenocarcinoma (OV) and exon skipping (ES) was the most important type. Univariate and multivariate Cox regression analysis were performed to identify survival-associated AS events and developed the prognostic model based on 11-AS events. The immune cells and different response to cytotoxic T lymphocyte associated antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1) blockers in low-risk and high-risk group of OV patients were analyzed. Ten kinds of immune cells were found up-regulated in low-risk group. Activated B cell, natural killer T cell, natural killer cell and regulatory T cell were associated with survival of OV. The patients in low-risk group had good response to CTLA-4 and PD-1 blockers treatment. Moreover, a regulatory network was established according to the correlation between AS events and splicing factors (SFs). The present study provided valuable insights into the underlying mechanisms of OV. AS events that were correlated with the immune system might be potential therapeutic targets. Citation Format: Guixi Zheng. Comprehensive characterization of 11 prognostic alternative splicing events in ovarian cancer interacted with the immune microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5010.
Abstract 3361: Distinct biological response of uterine corpus serous and endometrioid carcinomas to obesity may contribute to differences in clinical outcomes
Authors: Ignacio A. Wichmann, Fernán Gómez, Cristián Salazar, Felipe Suárez, Sumie Kato, Mauricio A. Cuello-Fredes
Journal: Cancer Research (2022)

Abstract Despite growing evidence linking obesity to the development and overall survival of cancer patients, the impact of increased body mass index (BMI) on gene expression patterns in gynecologic cancers is unclear. To address this, we herein downloaded RNAseq gene expression data from The Cancer Genome Atlas (TCGA) UCEC (uterine corpus endometrial carcinoma) dataset and matched it with clinical data entries including patient height and weight. We calculated BMI for each patient and used it to stratify patients as normoweight (BMI &amp;lt; 25), overweight (25 ≤ BMI &amp;lt; 30) or obese (BMI ≥ 30). BMI and nutritional status were matched to RNAseq gene expression data. Considering the known differences between endometrioid and serous uterine corpus tumors, analyses were performed separately for endometrioid (n = 356) and serous carcinomas (n = 117). Gene set enrichment analysis (GSEA) was performed between normoweight, overweight and obese patients. GSEA shows that tumors from obese patients display multiple dysregulated Gene Ontology (GO) terms (Biological Process, BP), which also differ between serous and endometrioid tumors. We further explored the impact of obesity on transcriptomic profiles of serous and endometrioid carcinomas by nutritional status independently by differential expression analysis using limma-voom. Significantly up- or downregulated genes were defined as those with logFC ≥ 1.5 at a non-adjusted P-value ≤ 0.01. Despite a clear enrichment or suppression of GO terms as evidenced by GSEA, transcriptomic analyses did not clearly separate patients according to their nutritional status. Therefore, obesity may impact on the dysregulation of biological processes through the cumulative effects of subtle differences in gene expression that, individually, do not seem to play a major role in oncogenesis. These results spotlight the relevance of obesity on the biology of uterine corpus cancers, which impact on the clinical course and treatment response of obese patients is yet to be determined. Funding: This work was supported by CONICYT FONDAP 15130011 (MC, IW), CONICYT-PFCHA/Doctorado Nacional 2019-Folio 21190421 (FG) and FONDECYT 1201083 (MC). Citation Format: Ignacio A. Wichmann, Fernán Gómez, Cristián Salazar, Felipe Suárez, Sumie Kato, Mauricio A. Cuello-Fredes. Distinct biological response of uterine corpus serous and endometrioid carcinomas to obesity may contribute to differences in clinical outcomes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3361.
Abstract 765: Hybridized-capture sequencing methods bias analysis of antigen presentation genes
Authors: Egmidio Medina, Katie Campbell, Antoni Ribas
Journal: Cancer Research (2022)

Abstract Introduction: Tumor-immune dynamics are often interrogated using hybridized capture-based sequencing approaches which require the use of baits that target the protein-coding regions of the genome. However, the genes encoding the antigen presentation machinery, including human leukocyte antigen (HLA) proteins, are very polymorphic, resulting in thousands of unique genotypes across patient cohorts. Here, using whole exome sequencing (WES) and hybridized capture-based RNA sequencing (RNAseq) from melanoma patients, we show that these genes are not uniformly assessed by common sequencing methods, and require careful analysis for accurate detection of copy number and somatic alterations. Methods: WES and RNAseq data was analyzed from 760 melanoma tumor biopsies, with WES derived from patient-matched normal blood samples. Coverage metrics for 26 antigen presentation genes, including classical and non-classical HLA genes, were evaluated, and the difference in coverage was calculated for heterozygous alleles. Each individual was assessed for heterozygous single nucleotide polymorphisms (SNPs) within each allele, and with respect to the haplotype of the human reference genome. Results: Focusing on the 26 genes assessed, HLA-A, HLA-B, HLA-C, and HLA-DRB1 were the most diverse across our patient cohort; there was an average of 134 unique pairs of HLA alleles in these genes. We compared the SNP profiles of allele combinations to the haplotype of the human reference genome, and observed four patterns: heterozygous alleles are similar to each other and the reference haplotype, heterozygous alleles are different from each other and different to the reference, alleles are very similar to each other and greatly differ from the reference, or one allele is more similar to the reference haplotype. The fourth pattern showed the greatest bias in sequencing, where the allele more similar to the human reference genome had a median 4-fold increase in coverage in normal WES data. Conclusions: Capture-based sequencing shows selection bias, as exome probes have been designed based upon the reported human reference genome, but results in selection bias in hybridized capture sequencing approaches. Alleles that have higher polymorphic differences with respect to the reference are not equally captured, resulting in nonuniform sequencing of heterozygous alleles. Citation Format: Egmidio Medina, Katie Campbell, Antoni Ribas. Hybridized-capture sequencing methods bias analysis of antigen presentation genes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 765.
Abstract 5119: Genomic landscape analysis in tumor tissue and circulating tumor DNA of Chinese patients with hepatocellular carcinoma
Authors: Dinghua Yang, Sheng Yu, Baitang Guo, Tingting Chen
Journal: Cancer Research (2022)

Abstract Background: Hepatocellular carcinoma (HCC) is a leading cause of tumor-associated death worldwide, owing to its high 5-year postoperative recurrence rate and heterogeneity. Although Molecular profiling has been used to predict prognosis and guide targeted therapy, obtaining liver tissue biopsies was still a clinical challenge of advanced HCC patients. Circulating tumor DNA (ctDNA) testing as a novel and convenient detecting techniques, which can revealed comprehensive information regarding to tumor genome profiles. The purpose of the study was to analyze and compare the genomic landscape characteristics of tumor tissue and ctDNA in Chinese HCC. Methods: 187 tumor tissue samples and 293 plasma samples from patients with HCC were collected from Nanfang hospital and 3DMed cohort, respectively. Next generation sequencing (NGS) assay (381/733 genes panel) was performed on tumor and plasma samples to capture tumor somatic single-nucleotide variants (SNVs). The gene variants information was summarized, analyzed and visualize using the maftools R package (Mayakonda et al. 2018.). Results: In total, DNA alterations were detected in 93.86% (275/293) plasma samples and 90.91% (170/187) in tumor samples, which variant levels included pathogenic, likely pathogenic and variant of uncertain significance. The most commonly altered genes in ctDNA results were TP53 (52%), TERT (24%), LRP1B (22%), FAT1 (15%), CTNNB1 (14%). While in HCC tumor testing results were TP53 (55%), TERT (27%), CTNNB1 (17%), SPTA1 (14%) and ARID1A (12%). Both the most variant classification was missense, next were frameshift indel. Both the top five affected pathways were TP53, RTK-RAS, NOTCH, WNT and Cell Cycle. In WNT pathway related genes, the highest alteration frequency tumor oncogene was CTNNB1, and suppressor gene was APC. We analyzed mutually exclusive and co-occurring event on top 25 mutated genes. In ctDNA analysis results, the probability of co-mutation between LRP1B and KMT2A gene was the highest (p &amp;lt; 0.001), while mutual exclusion between ARID1A and EGFR gene was the highest. Conclusion: Circulating tumor DNA mutation detection in HCC is feasible in the absence of HCC tissue DNA. The analysis results revealed the genomic landscape characteristics of blood-derived ctDNA in HCC were consistent with tumor tissues, which can provided HCC potential prognosis and treatment related genes information to further study. Citation Format: Dinghua Yang, Sheng Yu, Baitang Guo, Tingting Chen. Genomic landscape analysis in tumor tissue and circulating tumor DNA of Chinese patients with hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5119.
Abstract 2475: Visualization of cell to cell and cell to matrix interactions in the disruption of tumor-promoting desmoplasia by adoptive transfer of fibroblast activation protein targeted chimeric antigen receptor (CAR) T cells
Authors: Zebin Xiao, Leslie A. Hopper, Meghan C. Kopp, Emily McMillan, Yue Li, Richard L. Barrett, Ellen Puré
Journal: Cancer Research (2022)

Abstract The efficacy of chimeric antigen receptor (CAR) T-cell therapy in solid tumors is limited by inefficient T-cell infiltration, localization and hypofunctionality within the tumor microenvironment. Prior studies demonstrated that stromal cell targeted CAR T cells, in particular CAR T cells that target fibroblast activation protein (FAP), can effectively infiltrate, and inhibit tumor growth in mouse models of pancreatic ductal adenocarcinomas (PDAC) due to their capacity to deplete stromal cells and extracellular matrix (ECM) that otherwise present a barrier to adoptive cell therapies. However, the kinetics of tumor infiltration by FAP-CAR T cells, and the cell-cell and cell-matrix interactions that contribute to their anti-tumor activity are poorly understood. A better understanding FAP-CAR T-cell kinetics and intratumoral interactions should provide insights into the requirements for successful adoptive cell therapies in solid tumors. By combining immunostaining and real-time two-photon microscopy in tumor fragments of PDAC, we found that stromal cell targeted FAP-CAR T cells can efficiently traffic into tumors. Initially (days 1-3) FAP-CAR T cells were enriched in the stroma surrounding tumor nests but excluded from the tumor nests per se. While associated with the stroma rich region, the CAR T cells appeared activated and T cell motility was observed in loose collagen regions, but T cells migrated poorly in dense matrix areas. Aligned collagen fibers in the tumor boarder dictated the migratory trajectory of T cells and restricted them from entering tumor nests. By day 5 we observed depletion of immunosuppressive stromal cells, dissolution of the fibrillar collagen network surrounding tumor nests and infiltration of FAP-CAR T cells into tumor nests. Treatment with hyaluronidase increased the ability of T cells to infiltrate the tumor nest. Thus, FAP-CAR T cell-mediated ablation of immunosuppressive FAP+ stromal cells and disruption of the desmoplastic stroma they generate, can enhance accumulation and functionality of CAR-T cell therapy in the context of highly desmoplastic solid tumors. Citation Format: Zebin Xiao, Leslie A. Hopper, Meghan C. Kopp, Emily McMillan, Yue Li, Richard L. Barrett, Ellen Puré. Visualization of cell to cell and cell to matrix interactions in the disruption of tumor-promoting desmoplasia by adoptive transfer of fibroblast activation protein targeted chimeric antigen receptor (CAR) T cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2475.
Abstract 951: BNIP3L/NIX promotes breast cancer growth and metastasis by inducing epithelial-mesenchymal transition
Authors: Damian E. Berardi, Kay F. Macleod
Journal: Cancer Research (2022)

Abstract Mitophagy is induced in response to physiological stresses, including hypoxia, as an adaptive response that decreases mitochondrial mass to promote efficient use of limiting nutrients. BNIP3L/NIX is a mitophagy cargo receptor that integrates into the outer mitochondrial membrane where it interacts with processed LC3 at growing phagophore membranes to promote mitophagy. Our preliminary data shows that elevated BNIP3L/NIX expression in basal-like breast cancers correlates with worse overall patient survival. However, the functional significance of BNIP3L/NIX for growth and progression of breast cancer has not been determined. We generated a CRISPR/Cas9 KO BNIP3L/NIX 4T1 mouse mammary tumor model to determine how loss of BNIP3L/NIX affected tumor progression and metastasis. We observed that loss of BNIP3L/NIX decreased tumor cell growth and importantly attenuated metastasis to the lungs. By performing RNA-seq analysis, we found that these striking findings were associated with a decrease in molecular signatures expression of hypoxia-inducible genes and epithelial-mesenchymal transition (EMT) genes, including Twist and Vimentin. In addition, expression of Vimentin was complete ablated in 4T1 KO BNIP3L/NIX tumors in vivo and 4T1 KO BNIP3L/NIX tumor cells had significantly reduced ability to migrate and invade in vitro. Furthermore, CRISPR/Cas9-mediated deletion of HIF1α a in the 4T1 cell model reduced Vimentin expression in a manner dependent on BNIP3L/NIX expression. These results indicate that BNIP3L/NIX acts as an oncogene downstream of HIF1α in breast cancer by promoting expression of key EMT genes, stimulating tumor cell proliferation and migration, and that targeting BNIP3L/NIX might prove an effective strategy in the clinic. Citation Format: Damian E. Berardi, Kay F. Macleod. BNIP3L/NIX promotes breast cancer growth and metastasis by inducing epithelial-mesenchymal transition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 951.
Abstract 6110: Immune cell infiltrative characteristics reveals the superior efficacy of neoadjuvant immunochemotherapy versus chemotherapy alone in a real-world cohort of resectable non-small cell lung cancer
Authors: Wenhan Cai, Miao Jing, Jiaxin Wen, Yajun Gu, Xiaochen Zhao, Zhiqiang Xue
Journal: Cancer Research (2022)

Abstract We aimed to analyze the efficacy of neoadjuvant immunochemotherapy versus chemotherapy alone in the real-world settings, and to further explore tumor immune microenviroment (TIME), as well as its influence on response of neoadjuvant therapy in patients with NSCLC. Fifty-three patients with neoadjuvant therapy (immunochemotherapy, n=22; chemotherapy alone, n=31), resectable stage I~III, age≥18 years, and ECOG performance status 0-1 were recruited in the study. Fluorescent multiplex immunohistochemistry was performed by the automated quantitative pathology imaging system with tumor samples obtained in radical surgery. The major pathologic response (MPR) rate was significantly higher in patients with neoadjuvant immunochemotherapy than chemotherapy alone (p=.025; OR=4.222, 95% CI: 1.292~13.800). Patients received immunochemotherapy had higher pathologic complete response (pCR) rate than those with chemotherapy (p=.168; OR=3.150, 95% CI: 0.792~12.535). Compared with chemo alone, the tumor to stroma ratio of CD68+CD163- density was significantly elevated in patients subjected to immunochemotherapy (p=.0399). When patients were stratified by the pathologic response to neoadjuvant immunochemotherapy, the CD56dim in stroma significantly increased in patients achieved pCR than non-pCR (p=.038). The density of CD3+CD4+ cells (stroma, p=.039; total, p=.027) and CD20+ (total, p=.027) immune cells was significantly higher in patients achieved MPR than non-MPR. In patients administered with neoadjuvant chemotherapy alone, the expression level of PD-1 (p=.036), the density of FoxP3+ (stroma, p=.025; total, p=.013) and CD3+CD4+FoxP3+ (total, p=.042) cells significantly reduced in patients reached pCR. The density of CD20+ cells in stroma (p=.034) and the number of tertiary lymphoid structures (TLS; p=.006) were significantly higher in patients reached MPR. In conclusion, the therapeutic efficacy was improved by neoadjuvant immunochemotherapy in patients with NSCLC, which may be associated with the TIME remodeling, especially the migration of M1 macrophage from stroma to tumor islet. Clusters of NK, Th, Treg and B, PD-1, and TLS also play important role in response to neoadjuvant therapy. This work was supported by National Natural Science Foundation of China (NO. 62076254) Citation Format: Wenhan Cai, Miao Jing, Jiaxin Wen, Yajun Gu, Xiaochen Zhao, Zhiqiang Xue. Immune cell infiltrative characteristics reveals the superior efficacy of neoadjuvant immunochemotherapy versus chemotherapy alone in a real-world cohort of resectable non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6110.